US9738639B2 - Pyrroloquinoline quinone lithium salt crystal and preparation method and application thereof - Google Patents

Pyrroloquinoline quinone lithium salt crystal and preparation method and application thereof Download PDF

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US9738639B2
US9738639B2 US14/897,926 US201414897926A US9738639B2 US 9738639 B2 US9738639 B2 US 9738639B2 US 201414897926 A US201414897926 A US 201414897926A US 9738639 B2 US9738639 B2 US 9738639B2
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lithium salt
pqq
pyrroloquinoline quinine
pyrroloquinoline
crystalline form
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US20160137641A1 (en
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Chunjiu Zhong
Xuefeng Mei
Huan Zhang
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Shanghai Raising Pharmaceutical Co Ltd
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SHANGHAI RI XIN BIOTECHNOLOGY CO Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention is directed to a pyrroloquinoline quinine lithium salt crystal and preparation method and application thereof.
  • pyrroloquinoline quinine lithium salt is trilithium derivative of pyrroloquinoline quinine. Its formula is C 14 H 3 N 2 O 8 Li 3 , and molecular weight is 348. It has the following chemical structural:
  • a substance with the same chemical composition may crystallize with two or more different spatial lattice arrangements. This phenomenon is called polymorphism.
  • the polymorphic behavior of drugs can be of crucial importance in pharmacy and pharmacology, which takes tremendous impacts on drug quality. Varied crystalline forms may differ from each other with respect to one or more physical properties, such as crystal shape, melting point, hardness, solubility and dissociation, state stability and compaction behavior.
  • the differences in physical properties exhibited by polymorphs affect pharmaceutical parameters such as storage stability, bioavailability and efficacy. Therefore, new drug R&D should give more attention to the research on drug polymorphism and crystalline control.
  • PQQ is discovered as water-soluble B-vitamin by Japanese scientists at 2003. Mice deprived of PQQ grew poorly, have friable skin, develop abnormalities as osteolathyrism, have impaired immune function, are failed to reproduce and are prone to arthritis. Therefore, PQQ is identified as an essential nutrient in vivo. It is thought that PQQ has the same effect on human. Current techniques publish that the molecular weight of PQQ is 330. It is early discovered in microorganism, and it also exists in higher eukaryotes. Its crystalline structure and chemical synthesis are already clarified.
  • PQQ is a cofactor of multiply essential enzymes. PQQ may ameliorate the function of mitochondrial respiratory chain and the levels of free radicals in vivo. Studies indicate that PQQ deficient mice grow poorly, are failed to reproduce and are prone to arthritis. Therefore, PQQ is identified as an essential vitamin and nutrient in vivo.
  • PQQ has the following functions related with nervous system: (1) Antioxidant: strongly scavenging reactive oxygen species; (2) Alteration of the function of respiratory chain: maintaining the energy metabolism of mitochondria; (3) Activation of signal pathway: stimulating the release of nerve growth factor, recovering and promoting the growth of nerve; (4) Regulating the growth of somatic cells and effectively preventing liver impairment; (5) Attenuating the deposition of ⁇ -synuclein protein and preventing the fibrosis of nerve cells. Therefore, PQQ exhibits beneficial effect on treating neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease (AD).
  • AD Alzheimer's disease
  • Pyrroloquinoline quinine lithium salt has been proved to suppress the glycogen synthase kinase-3 activities (GSK-3) and has potential value for treating several mental diseases. Therefore, we pay more attention to the adverse application values of pyrroloquinoline quinine lithium salt. We try to find out its multifactorial mechanisms and apply it on preventing mental illness
  • the present invention is directed to pyrroloquinoline quinine lithium salt crystal and preparation method and application thereof.
  • the present invention discloses a crystal of pyrroloquinoline quinine lithium salt, characterized by an X-ray powder diffraction pattern with significant peaks at diffraction angles (2 ⁇ values) of about 6.222 ⁇ 0.2°, 7.379 ⁇ 0.2°, 7.941 ⁇ 0.2°, and 23.631 ⁇ 0.2°. Its endothermic peak is around 90-96° C. in the differential scanning calorimetry (DSC) thermogram. It shows peaks around 3396.03 cm ⁇ 1 , 1652.70 cm ⁇ 1 , 1604.48 cm ⁇ 1 , and 1355.71 cm ⁇ 1 on infrared spectroscopy (IR) pattern.
  • DSC differential scanning calorimetry
  • the pyrroloquinoline quinine lithium salt crystal is characterized by an X-ray powder diffraction pattern with more significant peaks at diffraction angles (2 ⁇ values) of about 24.044 ⁇ 0.2°, 25.497 ⁇ 0.2°, 27.541 ⁇ 0.2°, 30.736 ⁇ 0.2°, 32.306 ⁇ 0.2° and infrared spectroscopy (IR) pattern with more peaks around 1500.35 cm ⁇ 1 , 1243.86 cm ⁇ 1 , 1147.44 cm ⁇ 1 , 808.03 cm ⁇ 1 , 761.74 cm ⁇ 1 , 570.83 cm ⁇ 1 .
  • IR infrared spectroscopy
  • the compound stably exists as a nonahydrate by dynamic vapor sorption analysis. It forms monohydrate under the scope of relative humidity (RH) from 20% to 50%. It forms dihydrate under the scope of relative humidity (RH) from 70% to 100%.
  • the compound shows an endothermic peak of 93.33° C. in the differential scanning calorimetry (DSC) thermogram.
  • the present invention is directed to the process of preparing the pyrroloquinoline quinine lithium salt crystal of the following method: pyrroloquinoline quinine is mixed with lithium hydroxide (weight ratio 4:1), followed by adding organic solvent for continuous stirring for 2 hours at 0-5° C., then acetonitrile is added to the mixture (the ratio of acetonitrile to pyrroloquinoline quinine is 8 mL: 4 g), followed by stirring for 1 hour, precipitated intermediate A of pyrroloquinoline quinine lithium salt is collected by filtration.
  • the resultant intermediate A of pyrroloquinoline quinine lithium salt is dissolved in water, followed by adding tetrahydrofuran or isopropanol until complete mixed (the ratio of intermediate A of pyrroloquinoline quinine lithium salt, water and tetrahydrofuran or isopropanol is 10-1000 mg:0.5-20 mL:4-80 mL), the pyrroloquinoline quinine lithium salt crystal is obtained by standing overnight at room temperature.
  • the organic solvent is selected from the group consisting of ketones, ethers, aliphatic hydrocarbons, aromatic hydrocarbons, esters, nitriles, alcohols, halogenated hydrocarbons, and a combination of two or more thereof, which dissolves the raw material and does not ruin its structure.
  • the organic solvent is selected from the group consisting of methanol, ethanol, isopropanol, pentanol, acetone, 2-butanone, tetrahydrofuran, nitromethane, acetonitrile, chloroform, dichloromethane, methyl tert-butyl ether and a combination of two or more thereof.
  • the ratio of pyrroloquinoline quinine to organic solvent is 20 mg:1 mL.
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising the pyrroloquinoline quinine lithium salt crystal and at least any one form pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients are selected from fillers, disintegrants, binders, lubricants and a combination of two or more thereof.
  • the fillers are selected from starch, lactose, crystalline cellulose, dextrin, mannitol, oxidase, calcium sulfate and a combination of two or more thereof.
  • the disintegrants are selected from carboxymethylcellulose and its salt, crosslinked carboxymethylcellulose and its salt, crosslinked polyvinylpyrrolidone, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose and a combination of two or more thereof.
  • the binders are selected from polyvinylpyrrolidone, hydroxypropyl methyl cellulose, starch slurry and a combination of two or more thereof.
  • the lubricants are selected from magnesium stearate, calcium stearate and a combination of two or more thereof.
  • the present invention provides the application of the pyrroloquinoline quinine lithium salt crystal on preparing medicaments for treating memory impairments.
  • the present invention discloses crystalline form B of pyrroloquinoline quinine lithium salt, wherein the X-ray powder diffraction pattern, differential scanning calorimetry (DSC) thermogram, dynamic vapor sorption (DVS) curve and infrared spectroscopy (IR) pattern are fundamentally consistent with FIG. 1 , FIG. 2 , FIG. 3 and FIG. 4 , respectively.
  • the present invention is directed to the pyrroloquinoline quinine lithium salt crystal and preparation method and application thereof.
  • the pyrroloquinoline quinine lithium salt crystal could be used for preparing medicaments for treating memory impairments
  • FIG. 1 is a characteristic X-ray Powder Diffraction (XRPD) pattern for pyrroloquinoline quinine lithium salt crystal
  • FIG. 2 is a characteristic Differential Scanning Calorimetry (DSC) thermogram for pyrroloquinoline quinine lithium salt crystal
  • FIG. 3 is a characteristic Dynamic Vapor Sorption (DVS) curve for pyrroloquinoline quinine lithium salt crystal
  • FIG. 4 is a characteristic infrared spectroscopy (IR) pattern for pyrroloquinoline quinine lithium salt crystal.
  • X-ray powder diffraction (XRPD) patterns of the polymorphs are measured on a Bruker D2 phaser X-ray powder diffractometer using Cu-Ka radiation at room temperature.
  • the tube voltage and amperage ware set to 40 kV and 40 mA, respectively.
  • a theta-two theta continuous scan at 0.2 sec/step from 3° to 40° is used.
  • the pattern of crystalline is characteristic in X-ray powder diffraction pattern.
  • the band especially in low angle, can be slightly changed in the relative intensity depending on crystallization condition, particle size, relative concentration of mixture and other measurement condition. Therefore, the relative intensity of diffraction angle 2 ⁇ of the crystalline form is not characteristic.
  • the identification of crystalline form should be determined with the reference to the peak positions, but not their relative intensity. Additionally, the identification of crystalline form should not depend on one single peak, but comprehensive analysis of specific dI/II system. Moreover, during the identification of mixture, some deficiency of peak can occur due to the decline of sample concentration. Therefore, it is not necessary to find safe bands appeared in highly pure samples. Even a single band may identify the crystalline form.
  • DSC Differential Scanning Calorimetry
  • IR Infrared spectroscopy
  • Dynamic Vapor Sorption (DVS) curves of the polymorphs are measured on SMS DVS Intrinsic at 0-95% RH and 25° C.
  • the obtained sample is measured by differential scanning calorimetry (DSC), dynamic vapor sorption (DVS) and infrared spectroscopy (IR), respectively, as shown in FIG. 2, 3, 4 .
  • the compound shows an endothermic peak of 93.33° C. in the differential scanning calorimetry (DSC) thermogram. It shows peaks around 3396.03 cm ⁇ 1 , 1652.70 cm ⁇ 1 , 1604.48 cm ⁇ 1 , 1500.35 cm ⁇ 1 , 1355.71 cm ⁇ 1 , 1243.86 cm 1 , 1147.44 cm ⁇ 1 , 808.03 cm ⁇ 1 , 761.74 cm ⁇ 1 , 570.83 cm ⁇ 1 on infrared spectroscopy (IR) pattern.
  • the compound stably exists as a nonahydrate by dynamic vapor sorption analysis. It forms monohydrate under the scope of relative humidity (RH) from 20% to 50%. It forms dihydrate under the scope of relative humidity (RH) from 70% to 100%. It could forms polyhydrate with further increased relative humidity (RH).
  • crystalline form B of pyrroloquinoline quinine lithium salt 10 mg of the crystalline form A of pyrroloquinoline quinine lithium salt (bought from Shanghai Rixin Biological Co., Ltd) is dissolved in 1 mL of organic solvent (the mixture of methanol and methyl tert-butyl ether with the ratio of 1:1). The 0.7 mg of crystalline form B of pyrroloquinoline quinine lithium salt is obtained by standing overnight at room temperature. The obtained sample is measured by X-ray power diffraction, which shows the same peak pattern as example 1.
  • the hygroscopicity of the intermediate A of pyrroloquinoline quinine lithium salt and the crystalline form B of pyrroloquinoline quinine lithium salt from example 1 is measured by dynamic vapor sorption analysis.
  • DVS curve indicates that the hygroscopicity of the intermediate A of pyrroloquinoline quinine lithium salt from example 1 is 25.3% and 32.6% under the relative humidity (RH) of 65% and 80%, respectively.
  • RH relative humidity
  • the hygroscopicity of the crystalline form B of pyrroloquinoline quinine lithium salt is 8.4% and 13.9% under the relative humidity (RH) of 65% and 80%, respectively. Under the normal moist environment for storage, it shows hygroscopicity with a variety of 5-10%. The crystalline solid is not good.
  • the crystal of the present invention preferably contains 90% or more of a crystalline substance, more preferably 95% or more, further preferably 96% or more, more further preferably 97% or more, especially preferably 98% or more, most preferably 99% or more of a crystalline substance, which used in X-ray powder diffraction (XRPD), raman spectroscopy, infrared spectroscopy (IR).
  • XRPD X-ray powder diffraction
  • IR infrared spectroscopy
  • Example 5 A Pharmaceutical Composition Comprising the Pyrroloquinoline Quinine Lithium Salt Crystal
  • Crystalline form B of pyrroloquinoline quinine lithium salt is mixed with magnesium stearate and crystalline cellulose according to the following description:
  • Wild-type mice (Shanghai Slac Laboratory Animal Co., Ltd, weights of mice are From 16 g to 18 g, male, totally 10 mice) for group 1.
  • mice Model Animal Research Center of Nanjing University, weights of mice are from 30 g to 40 g, male, totally 60 mice). Sixty mice are randomized to six groups (group 2 to group 7) with ten mice for each group.
  • Group 7 low dosage of pyrroloquinoline quinine lithium salt
  • High dosage group of pyrroloquinoline quinine lithium salt 12 mL of solution A is obtained by dissolving 3.6 mg of crystalline form B of pyrroloquinoline quinine lithium salt in ddH 2 O.
  • Aricept group 0.15 mg/mL Aricept solution is obtained by grinding one tablet (5 mg) of Aricept into powder, followed by dissolved in 0.5% CMC (carboxymethylcellulose).
  • mice are training in Morris water maze, 30 minutes after drug administration. The training session lasts for 4 days. The probe test performed on the 5 th day.
  • the Morris water maze statistics software is used to automatically record and analyze the swimming trace in the quadrant, time spent and path in target or opposite quadrant occupancy and times of crossing platform.
  • the crystalline form B of pyrroloquinoline quinine lithium salt has good dose-dependent effects on APP/PS1 transgenic mice shown in Morris water maze test. It could significantly improved spatial memory and cognitive impairment of APP/PS1 transgenic mice.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
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  • Nitrogen Condensed Heterocyclic Rings (AREA)
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US14/897,926 2013-07-01 2014-06-23 Pyrroloquinoline quinone lithium salt crystal and preparation method and application thereof Active 2034-06-28 US9738639B2 (en)

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CN201310270885.2 2013-07-01
CN201310270885.2A CN103351387B (zh) 2013-07-01 2013-07-01 吡咯喹啉醌锂盐晶体及其制备方法和应用
CN201310270885 2013-07-01
PCT/CN2014/080542 WO2015000370A1 (fr) 2013-07-01 2014-06-23 Cristal de sel de lithium de pyrroloquinoléine-quinone, son procédé de préparation et son application

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JP2017114844A (ja) * 2015-12-22 2017-06-29 三菱瓦斯化学株式会社 認識能力向上食品
CN112274513B (zh) * 2020-12-28 2021-03-26 上海日馨生物科技有限公司 含有吡咯喹啉醌三锂盐九水化合物的药物组合物、胶囊剂及其制备方法

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CN101193888A (zh) 2005-03-24 2008-06-04 Clf医疗技术加速程序有限公司 吡咯喹啉醌（pqq）的合成方法
CN101851234A (zh) 2009-04-03 2010-10-06 上海日馨生物科技有限公司 吡咯喹啉醌锂盐衍生物及其制备方法
CN101885725A (zh) 2009-05-12 2010-11-17 江苏道琪生物科技有限公司 吡咯喹啉醌钠盐衍生物及其制备方法
JP2011026812A (ja) 2009-07-23 2011-02-10 Mano Kogyo Kk 引込管の施工方法

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WO2008029907A1 (fr) 2006-09-08 2008-03-13 Kyowa Hakko Bio Co., Ltd. Agent améliorant l'hypertension
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CN103351387B (zh) 2016-03-02
US20160137641A1 (en) 2016-05-19
EP2998305B1 (fr) 2020-04-08
PT2998305T (pt) 2020-07-09
WO2015000370A1 (fr) 2015-01-08
ES2794078T3 (es) 2020-11-17
EP2998305A4 (fr) 2017-01-04
JP2016522224A (ja) 2016-07-28
EP2998305A1 (fr) 2016-03-23
CN103351387A (zh) 2013-10-16
PL2998305T3 (pl) 2020-11-02
BR112015031797A2 (pt) 2017-07-25

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